Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

Wang, X; Finegan, Katherine G.; Robinson, Andrew C; Knowles, Lynette; Khosravi‐Far, Roya; Hinchliffe, Katherine A.; Boot-Handford, Raymond P.; Tournier, Cathy

doi:10.1038/sj.cdd.4401969

Cited by 52 publications

(54 citation statements)

References 41 publications

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“…Activated ERK1/2 also phosphorylates FOXO3a, leading to the degradation and subsequent inhibition of FOXO3a [38]. ERK5, another member of the MAP kinases that is often pro-survival [39,40], is also a negative regulator of FOXO3a and fibroblasts from ERK5 and MEK5 null mice display increased FOXO3a activity [28]. JNK regulates FOXO3a nuclear translocation in breast cancer cells after paclitaxel treatment [29].…”

Section: Discussionmentioning

confidence: 99%

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p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

Cai

Xia

2008

Apoptosis

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Sodium arsenite induces apoptosis in PC12 cells by activating the stress-activated p38 MAP kinase and the pro-apoptotic Bcl-2 family protein Bim EL . However, the relationship between p38 and Bim EL in this apoptosis has not been fully defined. Here, we report that sodium arsenite stimulates the protein expression and promoter activity of Bim EL in a p38-dependent manner. Sodium arsenite also caused nuclear translocation of FOXO3a, indicative of FOXO3a activation. Addition of a p38 inhibitor prevented FOXO3a nuclear translocation. RNAi knock down of FOXO3a inhibited Bim promoter activity, Bim EL protein expression, and arsenite-induced apoptosis. Our data identify p38 activation of FOXO3a and subsequent induction of Bim EL expression as a novel apoptotic mechanism. Together with our previous finding that Bim EL is phosphorylated and activated by p38, these results demonstrate that p38 induces apoptosis by regulating Bim EL at both the transcriptional and post-translational levels.

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Section: Discussionmentioning

confidence: 99%

“…Furthermore, other members of the MAP kinase family, such as JNK and ERK5, have been reported to directly or indirectly regulate FOXO3a expression [28,29]. To determine if FOXO3a plays a role in arsenite induction of Bim EL expression, we examined if FOXO3a is activated upon arsenite treatment.…”

Section: Foxo3a Mediates Sodium Arsenite-induced Bim Expressionmentioning

confidence: 99%

p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

Cai

Xia

2008

Apoptosis

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“…Generation of ERK5 loxP [19], Mox-2CRE [43] and CD4-CRE [50] mice has been described elsewhere. Mice were genotyped by ear biopsy and PCR (Fig.…”

Section: Animalsmentioning

confidence: 99%

“…Primary mouse embryonic fibroblasts (MEF) were isolated from ERK5 fl/fl /CreER 1 mice as described [19]. Cells were maintained in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 50 units/mL penicillin G and 50 mg/mL streptomycin (Invitrogen).…”

Section: Embryonic Fibroblast Culturementioning

confidence: 99%

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ERK5 regulation in naïve T‐cell activation and survival

et al. 2008

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ERK5 has been implicated in regulating the MEF2-dependent genes Klf2 and nur77 downstream of the TCR and the maintenance of expression of CD62L on peripheral T cells. Based on this data, knockout of ERK5 would be predicted to compromise T-cell development and the maintenance of T cells in the periphery. Using an ERK5 conditional knockout, driven by CD4-CRE or Vav-CRE transgenes resulting in the loss of ERK5 in T cells, we have found that ERK5 is not required for T-cell development. In addition, normal numbers of T cells were found in the spleens and lymph nodes of these mice. We also find that TCR stimulation is not a strong signal for ERK5 activation in primary murine T cells. ERK5 was found to contribute to the induction of Klf2 but not nur77 mRNA following TCR activation. Despite the reduction in Klf2 mRNA, no effect was seen in ERK5 knockouts on either the mRNA levels for the Klf2 target genes CD62L, CCR7 and S1P, or the cell surface expression of CD62L. These results suggest that while ERK5 does contribute to Klf2 regulation in T cells, it is not essential for the expression of CD62L or T-cell survival. IntroductionMitogen-activated protein kinase (MAPK) cascades are important mediators of cellular responses to a variety of signals, including growth factors, cytokines and cellular stresses. Fourteen MAPK isoforms have been identified in mammalian cells, which can broadly be divided into four groups, the classical MAPK (ERK1 and ERK2), p38 MAPK, JNK and atypical MAPK, which include ERK5, ERK3 and ERK8 [1][2][3][4][5].ERK5 is an unusual MAPK, as it contains a large C-terminal domain in addition to the MAPK domain [2,6,7]. The precise role of the C-terminal domain is unclear; however, it has been shown to be involved in the regulation of ERK5 sub-cellular localisation [8]. The C-terminal domain has also been suggested to act as a transcriptional co-activator for the MEF2 transcription factors [9]. In cells, ERK5 is activated in response to specific growth factors including EGF, as well as by some stresses, such as sorbitol and hydrogen peroxide [10,11]. Like other MAPK, ERK5 is activated by phosphorylation on its TXY motif downstream of a MAPK kinase. MEK5 was originally proposed as the kinase responsible for ERK5 activation, based on its interaction with ERK5 in a yeast two-hybrid assay [12]. This finding was later confirmed by the observation that embryonic fibroblasts isolated from MEK5 knockout mice were unable to activate ERK5 [13]. MEK5 is activated downstream of a MAPK kinase kinase Ã These authors contributed equally to this study. 2534(MAP3 K), most probably MEKK2. ERK5 signalling has been reported to be deficient in EGF and FGF stimulated embryonic fibroblast cells from MEKK2 knockout mice suggesting that MEKK2 is the predominant MAP3 K for MEK5, downstream of these signals [14,15]. It is not clear, however, if MEKK2 is the only MAP3 K able to activate the ERK5 pathway. Mouse knockouts of either ERK5 or MEK5 are embryonic lethal, however knockouts of MEKK2 are viable and do not exhibit obvious phen...

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Extracellular signal‐regulated kinases 2 (Erk2) and Erk5 in the central nervous system differentially contribute to central sensitization in male mice

Matsu'ura

Satoh

Itakura

et al. 2021

J of Neuroscience Research

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Nervous systems are designed to become extra sensitive to afferent nociceptive stimuli under certain circumstances such as inflammation and nerve injury. How pain hypersensitivity comes about is key issue in the field since it ultimately results in chronic pain. Central sensitization represents enhanced pain sensitivity due to increased neural signaling within the central nervous system (CNS). Particularly, much evidence indicates that underlying mechanism of central sensitization is associated with the change of spinal neurons. Extracellular signal-regulated kinases have received attention as key molecules in central sensitization. Previously, we revealed the isoform-specific function of extracellular signal-regulated kinase 2 (Erk2) in spinal neurons for central sensitization using mice with Cre-loxP-mediated deletion of Erk2 in the CNS. Still, how extracellular signal-regulated kinase 5 (Erk5) in spinal neurons contributes to central sensitization has not been directly tested, nor is the functional relevance of Erk5 and Erk2 known. Here, we show that Erk5 and Erk2 in the CNS play redundant and/or distinct roles in central sensitization, depending on the plasticity context (cell types, pain types, time, etc.). We used male mice with Erk5 deletion specifically in the CNS and found that Erk5 plays important roles in central sensitization in a formalin-induced inflammatory pain model. Deletion of both Erk2 and Erk5 leads to greater attenuation of central sensitization in this model, compared to deletion of either isoform alone. Conversely, Erk2 but not Erk5 plays important roles in central sensitization in neuropathic pain, a type of chronic pain caused by nerve damage. Our results suggest the elaborate mechanisms of Erk signaling in central sensitization.

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Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress

Cited by 52 publications

References 41 publications

p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

ERK5 regulation in naïve T‐cell activation and survival

Extracellular signal‐regulated kinases 2 (Erk2) and Erk5 in the central nervous system differentially contribute to central sensitization in male mice

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